DJ-1 is one of the rarest gene mutations associated with recessive parkinsonism. Although the function of the DJ-1 protein, which is conserved in aerobic species from E coli to man, is unknown, several observations suggest that it plays a key role in cellular responses to oxidative stress. Several previous studies have suggested that oxidative stress is associated with aging in most aerobic systems. Therefore, our aim in this project is to understand why mutations in such an evolutionarily ancient protein would be associated with age related neurodegeneration of dopaminergic neurons, as seen in Parkinsons disease. In mammalian cells, one of the major sources of reactive oxygen species and associated stress is mitochondria, which can leak electrons if uncoupled. Therefore, in a series of publications we have shown that presence or absence of DJ-1 can modify mitochondrial function and responses to oxidative damage. Specifically, we have shown that cells deficient in DJ-1 are more sensitive to stressors that inhibit mitochondrial complex I activity and indirectly generate free radicals. This results in mitochondria with lower membrane potential that are cleared by autophagy. We also showed that DJ-1 is not directly in the same pathway as PINK1 and parkin, two other genes for recessive parkinsonism, but works in parallel. We are currently extending these studies to look in more depth at the phenotype of DJ-1 deficient mice including in neuronal cells derived from these animals. We are attempting to rescue mitochondrial effects with mutations that should attenuate or enhance the response of DJ-1 to oxidation.